The primary aim of this project is to evaluate the contributions of the serotonergic neurotransmitter system to human behavior. Most of the studies described in this project report have been carried out in healthy human volunteers or selected patient groups who have disorders other then obsessive-compulsive disorder (OCD). (Our broader range of studies in OCD patients are described in another project report). The projects have, by necessity, used less direct approaches to serotonin system evaluation than do our animal studies on serotonergic function. In the past year, we have found that repeated administration of a serotonin agonist m-chlorophenylpiperazine (m-CPP) leads to an essentially complete absence of the effects of the agonist on behavior, and a significant attenuation of its effects on temperature, blood pressure and neuroendocrine measures. Studies in animals and limited data from humans indicate that tolerance following repeated administration of this serotonin agonist results from a desensitization of serotonin 2C receptors, and that a similar serotonic 2C receptor desensitization follows repeated administration of serotonin reuptake inhibiting antidepressants, such as fluoxetine. In other studies, long-term fluoxetine treatment was found to be associated with reduced hallucinations and other responses to LSD, and that fluoxetine administration proved to be an effective treatment for premenstrual dysphoria. The selective serotonin 3 receptor antagonist, ondansetron, was found to attenuate responses to d-amphetamine and to m-chlorophenylpiperazine, but did not alter responses to pentagastrin or scopolamine.